The goal of these investigations is to provide insight into the etiology and pathogenesis of the cholinergic dysfunction of Alzheimer's Disease and some other dementing disorders, and to attempt to use some of the information obtained to improve the accuracy of differential diagnosis. In the next project period we plan to expand our studies of ventral forebrain cholinergic neurons innervating cerebral cortex and hippocampus, because it is now well established that these cells dysfunction and perhaps degenerate in cases of Alzheimer's Disease and some, but not all, other dementing disorders. Using monoclonal antibodies to proteins apparently unique to these cells, we will test the hypothesis that dysfunction of these cells can be detected by reduced concentrations of these antigens, and will determine if they are present in detectable amounts in blood and spinal fluid, and whether or not there are quantitative or qualitative abnormalities that can be used as aids to the differential diagnosis of Alzheimer's Disease. Because of the well-established links between Alzheimer's Disease and Down's Syndrome, we will test the hypothesis that there are quantitative or qualitative abnormalities of proteins from chromosome 21 in patients with Alzheimer's Disease. If any of the above studies reveal consistent qualitative or quantitative differences between Alzheimer patients and normals, we will clone the gene or genes coding for the appropriate proteins, and carry out studies of gene structure and expression. A speculative model for the pathogenesis of cholinergic dysfunction has been constructed, and this has led to the development of two simple and testable hypotheses. We will test these by screening blood, spinal fluid and brain tissue from appropriate cases for the presence of endogenous compounds with muscarinic antagonist-like properties, or the ability inhibit high affinity choline uptake systems.